This study investigates whether highly pathogenic avian influenza A/H5N1 virus can acquire the ability to be transmitted between mammals, including humans, through aerosols or respiratory droplets. The researchers genetically modified the A/H5N1 virus by site-directed mutagenesis and serial passage in ferrets. They found that the virus acquired mutations, including four amino acid substitutions in the host receptor-binding protein hemagglutinin (HA) and one in the polymerase complex protein basic polymerase 2 (PB2), which consistently appeared in airborne-transmitted viruses. These viruses were sensitive to the antiviral drug oseltamivir and reacted well with antisera raised against H5 influenza vaccine strains. The study concludes that avian A/H5N1 influenza viruses can acquire the capacity for airborne transmission between mammals without recombination in an intermediate host, posing a risk for human pandemic influenza.This study investigates whether highly pathogenic avian influenza A/H5N1 virus can acquire the ability to be transmitted between mammals, including humans, through aerosols or respiratory droplets. The researchers genetically modified the A/H5N1 virus by site-directed mutagenesis and serial passage in ferrets. They found that the virus acquired mutations, including four amino acid substitutions in the host receptor-binding protein hemagglutinin (HA) and one in the polymerase complex protein basic polymerase 2 (PB2), which consistently appeared in airborne-transmitted viruses. These viruses were sensitive to the antiviral drug oseltamivir and reacted well with antisera raised against H5 influenza vaccine strains. The study concludes that avian A/H5N1 influenza viruses can acquire the capacity for airborne transmission between mammals without recombination in an intermediate host, posing a risk for human pandemic influenza.